Malte Gersch
@maltegersch.bsky.social
Chemical Biologist & Research Groupleader at Max Planck & TU Dortmund. Interested in DUBs, proteases, ubiquitin, the outdoors and more. Views are my own. cgc.mpg.de/gersch
Pinned
Malte Gersch
@maltegersch.bsky.social
· May 5
Chimeric deubiquitinase engineering reveals structural basis for specific inhibition of the mitophagy regulator USP30 - Nature Structural & Molecular Biology
Kazi et al. report the crystal structure of the mitochondrial deubiquitinase USP, a clinical stage Parkinson’s disease drug target, in complex with a specific inhibitor. The authors delineate a framew...
www.nature.com
Super happy to share that our work on the specific inhibition of USP30 - a clinical stage Parkinson's drug target - is now online at NSMB www.nature.com/articles/s41... Have a read if you fancy chimeric protein engineering or a framework for DUB ligandability. Huge congratulations to Nafizul & team!
Reposted by Malte Gersch
Our nuclease-protease story is out! We explored a fascinating case of coevolution and modularity in prokaryotic immune systems: www.science.org/doi/10.1126/...
Thanks to wonderful coauthors/collaborators/friends, the whole @doudna-lab.bsky.social and everyone at @innovativegenomics.bsky.social
Thanks to wonderful coauthors/collaborators/friends, the whole @doudna-lab.bsky.social and everyone at @innovativegenomics.bsky.social
Recurrent acquisition of nuclease-protease pairs in antiviral immunity
Antiviral immune systems diversify by integrating new genes into existing pathways, creating new mechanisms of viral resistance. We identified genes encoding a predicted nuclease paired with a trypsin...
www.science.org
November 13, 2025 at 10:15 PM
Our nuclease-protease story is out! We explored a fascinating case of coevolution and modularity in prokaryotic immune systems: www.science.org/doi/10.1126/...
Thanks to wonderful coauthors/collaborators/friends, the whole @doudna-lab.bsky.social and everyone at @innovativegenomics.bsky.social
Thanks to wonderful coauthors/collaborators/friends, the whole @doudna-lab.bsky.social and everyone at @innovativegenomics.bsky.social
Reposted by Malte Gersch
We call these mechanism based sirtuin inhibitors SirTraps that trap the enzyme via this ADP ribose adduct onlinelibrary.wiley.com/doi/10.1002/... 2/
From Pharmacophore to Warhead: NAD+‐Targeting Triazoles as Mechanism‐Based Sirtuin Inhibitors
We report “Sirtuin Trapping Ligands” (SirTraps), mechanism-based 1,2,3-triazole inhibitors that hijack sirtuin (SIRT) catalysis to form covalent triazolium– or triazole–ADP-ribose (ADPR) adducts from...
onlinelibrary.wiley.com
November 2, 2025 at 1:20 PM
We call these mechanism based sirtuin inhibitors SirTraps that trap the enzyme via this ADP ribose adduct onlinelibrary.wiley.com/doi/10.1002/... 2/
Reposted by Malte Gersch
A #postdoc position in atypical #ubiquitin signalling and protein binder engineering is opening soon in my lab at DTU Bioengineering! Get in touch if you are interested.
October 30, 2025 at 2:13 PM
A #postdoc position in atypical #ubiquitin signalling and protein binder engineering is opening soon in my lab at DTU Bioengineering! Get in touch if you are interested.
Reposted by Malte Gersch
Excited to share the peer-reviewed version of our work, now online in @embojournal.org! Big thanks to our reviewers and @hvodermaier.bsky.social for facilitating this process. Looking forward to continuing this fun collaboration with @michaelnadbio.bsky.social!
www.embopress.org/doi/full/10....
www.embopress.org/doi/full/10....
October 30, 2025 at 3:33 PM
Excited to share the peer-reviewed version of our work, now online in @embojournal.org! Big thanks to our reviewers and @hvodermaier.bsky.social for facilitating this process. Looking forward to continuing this fun collaboration with @michaelnadbio.bsky.social!
www.embopress.org/doi/full/10....
www.embopress.org/doi/full/10....
Reposted by Malte Gersch
Also enjoyed reading the News & Views from @maltegersch.bsky.social, which beautifully summarizes the recent advancements in studying MARUbylation as a novel hybrid PTM.
www.nature.com/articles/s41...
www.nature.com/articles/s41...
ADPr gets a ubiquitin upgrade - Nature Chemical Biology
MARUbylation is a hybrid post-translational protein modification in which mono-ADP-ribosylation acts as a scaffold for sequential mono- and polyubiquitylation. Recent studies illuminate its substrates...
www.nature.com
October 30, 2025 at 3:41 PM
Also enjoyed reading the News & Views from @maltegersch.bsky.social, which beautifully summarizes the recent advancements in studying MARUbylation as a novel hybrid PTM.
www.nature.com/articles/s41...
www.nature.com/articles/s41...
Reposted by Malte Gersch
Check out our new publication, a collaboration with Giovanni Luchetti and Vishva Dixit @ Genentech.
We show that the E.coli effector NleL inhibits intestinal epithelial cell extrusion after #inflammasome activation via degrading the kinases ROCK1 and 2!!
www.nature.com/articles/s41...
Explainer 1/8
We show that the E.coli effector NleL inhibits intestinal epithelial cell extrusion after #inflammasome activation via degrading the kinases ROCK1 and 2!!
www.nature.com/articles/s41...
Explainer 1/8
Enteropathogenic bacteria evade ROCK-driven epithelial cell extrusion - Nature
The bacterial ubiquitin ligase NleL evades host defence mechanisms both by inhibiting pyroptosis and by preventing infected intestinal epithelial cells from being extruded into the lumen and expelled ...
www.nature.com
October 22, 2025 at 3:47 PM
Check out our new publication, a collaboration with Giovanni Luchetti and Vishva Dixit @ Genentech.
We show that the E.coli effector NleL inhibits intestinal epithelial cell extrusion after #inflammasome activation via degrading the kinases ROCK1 and 2!!
www.nature.com/articles/s41...
Explainer 1/8
We show that the E.coli effector NleL inhibits intestinal epithelial cell extrusion after #inflammasome activation via degrading the kinases ROCK1 and 2!!
www.nature.com/articles/s41...
Explainer 1/8
Reposted by Malte Gersch
🚨Our paper is out! 🥳
Hijacking a bacterial ABC transporter for efficient genetic code expansion.
Many congrats to everyone involved - a multi-year effort led by @taruniype.bsky.social @maxfottner.bsky.social
www.nature.com/articles/s41...
it all started years ago with a failed experiment
🧵👇 1/9
Hijacking a bacterial ABC transporter for efficient genetic code expansion.
Many congrats to everyone involved - a multi-year effort led by @taruniype.bsky.social @maxfottner.bsky.social
www.nature.com/articles/s41...
it all started years ago with a failed experiment
🧵👇 1/9
Hijacking a bacterial ABC transporter for genetic code expansion - Nature
Bacterial ATP-binding cassette (ABC) transporters can be utilized and engineered to transport non-canonical amino acids into Escherichia coli for highly efficient synthesis of proteins with novel func...
www.nature.com
October 16, 2025 at 2:06 PM
🚨Our paper is out! 🥳
Hijacking a bacterial ABC transporter for efficient genetic code expansion.
Many congrats to everyone involved - a multi-year effort led by @taruniype.bsky.social @maxfottner.bsky.social
www.nature.com/articles/s41...
it all started years ago with a failed experiment
🧵👇 1/9
Hijacking a bacterial ABC transporter for efficient genetic code expansion.
Many congrats to everyone involved - a multi-year effort led by @taruniype.bsky.social @maxfottner.bsky.social
www.nature.com/articles/s41...
it all started years ago with a failed experiment
🧵👇 1/9
Reposted by Malte Gersch
You’ve heard of ubiquitination, meet deazaguanylation: Doug Wassarman in our lab discovered phage defense pathways have co-opted Q nucleobase biosynthetic enzymes to catalyze a new form of protein conjugation chemistry @science.org
www.science.org/doi/10.1126/...
www.science.org/doi/10.1126/...
September 25, 2025 at 7:16 PM
You’ve heard of ubiquitination, meet deazaguanylation: Doug Wassarman in our lab discovered phage defense pathways have co-opted Q nucleobase biosynthetic enzymes to catalyze a new form of protein conjugation chemistry @science.org
www.science.org/doi/10.1126/...
www.science.org/doi/10.1126/...
Reposted by Malte Gersch
Allosteric activation of a ubiquitin ligase by an internal kinase domain! Congratulations to our team member Thornton Fokkens for this fascinating discovery in a neglected disease area with strong therapeutic need. Many thanks to all our great collaborators!
www.sciencedirect.com/science/arti...
www.sciencedirect.com/science/arti...
A Leishmania virulence factor harnesses an allosteric kinase switch to regulate its ubiquitin ligase activity
Stringent control of ubiquitylation is a central requirement of signaling specificity in eukaryotes. Here, we discover a domain module integrating pro…
www.sciencedirect.com
September 24, 2025 at 3:30 PM
Allosteric activation of a ubiquitin ligase by an internal kinase domain! Congratulations to our team member Thornton Fokkens for this fascinating discovery in a neglected disease area with strong therapeutic need. Many thanks to all our great collaborators!
www.sciencedirect.com/science/arti...
www.sciencedirect.com/science/arti...
Reposted by Malte Gersch
How can mitophagy be an effective quality control mechanism if mtDNA mutations reach high enough levels to cause disease?
This question led us into a dark path, full of concepts of evolutionary genetics, germline stem cell biology and mito-nuclear compatibility.
www.science.org/doi/10.1126/...
This question led us into a dark path, full of concepts of evolutionary genetics, germline stem cell biology and mito-nuclear compatibility.
www.science.org/doi/10.1126/...
Ubiquitin-mediated mitophagy regulates the inheritance of mitochondrial DNA mutations
Mitochondrial synthesis of adenosine triphosphate is essential for eukaryotic life but is dependent on the cooperation of two genomes: nuclear and mitochondrial DNA (mtDNA). mtDNA mutates ~15 times as...
www.science.org
October 10, 2025 at 8:45 AM
How can mitophagy be an effective quality control mechanism if mtDNA mutations reach high enough levels to cause disease?
This question led us into a dark path, full of concepts of evolutionary genetics, germline stem cell biology and mito-nuclear compatibility.
www.science.org/doi/10.1126/...
This question led us into a dark path, full of concepts of evolutionary genetics, germline stem cell biology and mito-nuclear compatibility.
www.science.org/doi/10.1126/...
Reposted by Malte Gersch
Just out in @science.org: Together with the lab of @wilhelmpalm.bsky.social, we used sequential in-vitro/in-vivo CRISPR screens to decipher metabolic adaptations in tumors. We find that acidosis is a dominant factor that shapes energy metabolism and stress resilience. www.science.org/doi/10.1126/...
October 9, 2025 at 7:37 PM
Just out in @science.org: Together with the lab of @wilhelmpalm.bsky.social, we used sequential in-vitro/in-vivo CRISPR screens to decipher metabolic adaptations in tumors. We find that acidosis is a dominant factor that shapes energy metabolism and stress resilience. www.science.org/doi/10.1126/...
Reposted by Malte Gersch
new preprint: Ubiquitin is a protein modification linked with degradation but known to regulate other functions. Over 100k ubiquitination sites have been discovered and here we (@julianvangerwen.bsky.social + others) try to prioritize those most critical to the cell www.biorxiv.org/content/10.1...
The functional landscape of the human ubiquitinome
Protein ubiquitination regulates cell biology through diverse avenues, from quality control-linked protein degradation to signaling functions such as modulating protein-protein interactions and enzyme...
www.biorxiv.org
October 9, 2025 at 7:07 AM
new preprint: Ubiquitin is a protein modification linked with degradation but known to regulate other functions. Over 100k ubiquitination sites have been discovered and here we (@julianvangerwen.bsky.social + others) try to prioritize those most critical to the cell www.biorxiv.org/content/10.1...
Reposted by Malte Gersch
Are you using DIA mass spectrometry in proteomics?
We have just put this paper online: www.biorxiv.org/content/10.1...
Here, we came up with some Recommendations for Quantitative Data-Independent Acquisition (DIA) Proteomics using Controlled Quantitative Experiments (CQEs)
1/4
We have just put this paper online: www.biorxiv.org/content/10.1...
Here, we came up with some Recommendations for Quantitative Data-Independent Acquisition (DIA) Proteomics using Controlled Quantitative Experiments (CQEs)
1/4
Recommendations for Quantitative Data-Independent Acquisition (DIA) Proteomics using Controlled Quantitative Experiments (CQEs)
Advances in mass spectrometry and associated computational tools have resulted in the wide-spread adoption of Data-Independent Acquisition (DIA) for proteomics. Experiments using state-of-the-art inst...
eur03.safelinks.protection.outlook.com
September 23, 2025 at 9:44 AM
Are you using DIA mass spectrometry in proteomics?
We have just put this paper online: www.biorxiv.org/content/10.1...
Here, we came up with some Recommendations for Quantitative Data-Independent Acquisition (DIA) Proteomics using Controlled Quantitative Experiments (CQEs)
1/4
We have just put this paper online: www.biorxiv.org/content/10.1...
Here, we came up with some Recommendations for Quantitative Data-Independent Acquisition (DIA) Proteomics using Controlled Quantitative Experiments (CQEs)
1/4
Reposted by Malte Gersch
A new paper reports direct ubiquitination of a small molecule BRD1732 in cells. BR31732 ubiquitination is E3 ligase-dependent and leads to inhibition of proteasomal degradation.
www.nature.com/articles/s41...
www.nature.com/articles/s41...
Highly specific intracellular ubiquitination of a small molecule - Nature Chemical Biology
Li et al. discovered that the cytotoxic synthetic small molecule BRD1732 is directly ubiquitinated in cells. Ubiquitination of BRD1732 is E3 ligase dependent and leads to inhibition of proteasomal deg...
www.nature.com
August 21, 2025 at 4:25 PM
A new paper reports direct ubiquitination of a small molecule BRD1732 in cells. BR31732 ubiquitination is E3 ligase-dependent and leads to inhibition of proteasomal degradation.
www.nature.com/articles/s41...
www.nature.com/articles/s41...
Reposted by Malte Gersch
For life to emerge on Earth, peptides must first have formed without the aid of enzymes — but how? Reactions of sulfur-containing molecules might have been key
go.nature.com/4oX04jC
go.nature.com/4oX04jC
Origins of life: the molecules that could have unlocked peptide synthesis
For life to emerge on Earth, peptides must first have formed without the aid of enzymes — but how? Reactions of sulfur-containing molecules might have been key.
go.nature.com
August 28, 2025 at 9:01 AM
For life to emerge on Earth, peptides must first have formed without the aid of enzymes — but how? Reactions of sulfur-containing molecules might have been key
go.nature.com/4oX04jC
go.nature.com/4oX04jC
Reposted by Malte Gersch
Delighted to share our work on cellular ubiquitination of drug-like compounds by HUWE1 - a surprising journey! Kudos to all contributors & first authors, Barbara Orth and Pavel Pohl. Sincere thanks to @ireserra.bsky.social #NatCommun for expertly guiding the winding publishing path.
rdcu.be/eDzPk
rdcu.be/eDzPk
Selective ubiquitination of drug-like small molecules by the ubiquitin ligase HUWE1
Nature Communications - Ubiquitination is a versatile modification system in eukaryotic cells. Here, the authors unveil that the ubiquitin ligase HUWE1 can modify drug-like small-molecule...
rdcu.be
September 2, 2025 at 11:55 AM
Delighted to share our work on cellular ubiquitination of drug-like compounds by HUWE1 - a surprising journey! Kudos to all contributors & first authors, Barbara Orth and Pavel Pohl. Sincere thanks to @ireserra.bsky.social #NatCommun for expertly guiding the winding publishing path.
rdcu.be/eDzPk
rdcu.be/eDzPk
Reposted by Malte Gersch
Fully‐Functionalized Natural Product Probes to Expand the Chemical Tractability of the Human Proteome onlinelibrary.wiley....
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#proteomics #prot-paper
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#proteomics #prot-paper
September 13, 2025 at 9:20 AM
Fully‐Functionalized Natural Product Probes to Expand the Chemical Tractability of the Human Proteome onlinelibrary.wiley....
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#proteomics #prot-paper
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#proteomics #prot-paper
Reposted by Malte Gersch
This one is a bit of a departure from the usual and definitely a work in progress!
We found that by using ab initio reconstruction at very high res, in very small steps, we could crack some small structures that had eluded us - e.g. 39kDa iPKAc (EMPIAR-10252), below.
Read on for details... 1/x
We found that by using ab initio reconstruction at very high res, in very small steps, we could crack some small structures that had eluded us - e.g. 39kDa iPKAc (EMPIAR-10252), below.
Read on for details... 1/x
September 13, 2025 at 12:05 AM
This one is a bit of a departure from the usual and definitely a work in progress!
We found that by using ab initio reconstruction at very high res, in very small steps, we could crack some small structures that had eluded us - e.g. 39kDa iPKAc (EMPIAR-10252), below.
Read on for details... 1/x
We found that by using ab initio reconstruction at very high res, in very small steps, we could crack some small structures that had eluded us - e.g. 39kDa iPKAc (EMPIAR-10252), below.
Read on for details... 1/x
Reposted by Malte Gersch
The BUB1 and BUBR1 paralogs scaffold the kinetochore fibrous corona | Science Advances www.science.org/doi/10.1126/...
Congratulations @vcmentowski.bsky.social for solving a remarkably challenging molecular puzzle
Congratulations @vcmentowski.bsky.social for solving a remarkably challenging molecular puzzle
The BUB1 and BUBR1 paralogs scaffold the kinetochore fibrous corona
The kinetochore fibrous corona docks on CENP-E and a second elusive receptor identified as the checkpoint protein BUB1.
www.science.org
September 15, 2025 at 4:50 AM
The BUB1 and BUBR1 paralogs scaffold the kinetochore fibrous corona | Science Advances www.science.org/doi/10.1126/...
Congratulations @vcmentowski.bsky.social for solving a remarkably challenging molecular puzzle
Congratulations @vcmentowski.bsky.social for solving a remarkably challenging molecular puzzle
Reposted by Malte Gersch
Covariation MS uncovers a protein that controls cysteine catabolism
www.nature.com/articles/s41...
Beautiful work from Ed Chouchani!
www.nature.com/articles/s41...
Beautiful work from Ed Chouchani!
Covariation MS uncovers a protein that controls cysteine catabolism - Nature
A mass spectrometry-based approach globally identifies protein regulators of metabolism and reveals the role of LRRC58 in controlling cysteine catabolism.
www.nature.com
September 17, 2025 at 4:15 PM
Covariation MS uncovers a protein that controls cysteine catabolism
www.nature.com/articles/s41...
Beautiful work from Ed Chouchani!
www.nature.com/articles/s41...
Beautiful work from Ed Chouchani!
Reposted by Malte Gersch
Targeted DNA ADP-ribosylation triggers templated repair in bacteria and base mutagenesis in eukaryotes - @helmholtz-hiri.bsky.social go.nature.com/4n7zDpG
Targeted DNA ADP-ribosylation triggers templated repair in bacteria and base mutagenesis in eukaryotes - Nature Biotechnology
Append editing of ADP-ribosyl to thymine is used for precise modifications in bacteria and eukaryotes.
go.nature.com
September 4, 2025 at 3:20 PM
Targeted DNA ADP-ribosylation triggers templated repair in bacteria and base mutagenesis in eukaryotes - @helmholtz-hiri.bsky.social go.nature.com/4n7zDpG
Reposted by Malte Gersch
New paper alert! Stellar work by brilliant lead first author @annaleder.bsky.social together with project leader @masgu.bsky.social reveals a groundbreaking discovery: PDIA6 forms multi-chaperone condensates creating "folding factories" in the ER. www.nature.com/articles/s41...
August 11, 2025 at 9:10 AM
New paper alert! Stellar work by brilliant lead first author @annaleder.bsky.social together with project leader @masgu.bsky.social reveals a groundbreaking discovery: PDIA6 forms multi-chaperone condensates creating "folding factories" in the ER. www.nature.com/articles/s41...
Reposted by Malte Gersch
Excited to share our latest work developing molecular glue degraders of ZBTB11, now out in @natchembio.nature.com
www.nature.com/articles/s41...
www.nature.com/articles/s41...
ZBTB11 depletion targets metabolic vulnerabilities in KRAS inhibitor-resistant PDAC - Nature Chemical Biology
Depletion of a transcriptional factor ZBTB11 using molecular glue degraders can overcome oxidative-phosphorylation-mediated KRAS inhibitor resistance in pancreatic ductal adenocarcinoma with low acute...
www.nature.com
August 11, 2025 at 1:51 PM
Excited to share our latest work developing molecular glue degraders of ZBTB11, now out in @natchembio.nature.com
www.nature.com/articles/s41...
www.nature.com/articles/s41...
Reposted by Malte Gersch
Excited to share our latest: we engineered the reactivity of a bacterial E1-like enzyme for ATP-driven modification of C termini. Our tool mimics the logic of peptide bond formation in biology for precision modification of proteins in vitro. 🧪https://rdcu.be/ewN7C
Engineered reactivity of a bacterial E1-like enzyme enables ATP-driven modification of protein and peptide C termini
Nature Chemistry - In living systems, ATP provides an energetic driving force for protein synthesis and modification. Now, an engineered enzymatic tool has been developed for high-yield, ATP-driven...
rdcu.be
July 18, 2025 at 2:40 PM
Excited to share our latest: we engineered the reactivity of a bacterial E1-like enzyme for ATP-driven modification of C termini. Our tool mimics the logic of peptide bond formation in biology for precision modification of proteins in vitro. 🧪https://rdcu.be/ewN7C
Reposted by Malte Gersch
This has a neat mechanism of inhibition:
www.nature.com/articles/s41...
www.nature.com/articles/s41...
SuFEx-based antitubercular compound irreversibly inhibits Pks13 - Nature
A preclinical covalent compound, CMX410, contains a aryl fluorosulfate warhead that targets the acyltransferase domain of Mtb Pks13, an essential enzyme in cell-wall biosynthesis, making it a pro...
www.nature.com
July 30, 2025 at 8:12 PM
This has a neat mechanism of inhibition:
www.nature.com/articles/s41...
www.nature.com/articles/s41...